JP2020513248A - Affinity cell extraction by sound - Google Patents

Affinity cell extraction by sound Download PDF

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JP2020513248A
JP2020513248A JP2019543176A JP2019543176A JP2020513248A JP 2020513248 A JP2020513248 A JP 2020513248A JP 2019543176 A JP2019543176 A JP 2019543176A JP 2019543176 A JP2019543176 A JP 2019543176A JP 2020513248 A JP2020513248 A JP 2020513248A
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ligand
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ナタリア ロディオノワ，
ナタリア ロディオノワ，
ベン ロス−ヨンスル，
ベン ロス−ヨンスル，
バルト リプケンス，
バルト リプケンス，
ルドルフ ギルマンシン，
ルドルフ ギルマンシン，
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Flodesign Sonics Inc
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Abstract

機能性物質が塗工されたビーズは、そのビーズを捕捉または通過させる音響場にさらされる。ビーズは、強磁性物質を含んでも含まなくてもよい。ビーズは、ホストに対して生体適合性があってもよく、生分解性があってもよい。ビーズのサイズはある範囲にわたって変化してもよく、および／または、不均一または均一であってもよい。ビーズの組成は、高、中または低の音響コントラスト物質を含んでもよい。機能性物質の化学的性質は、既存のプロセスと互換性があってもよい。The beads coated with the functional substance are exposed to an acoustic field that captures or passes the beads. The beads may or may not include a ferromagnetic material. The beads may be biocompatible with the host or biodegradable. The size of the beads may vary over a range and / or may be non-uniform or uniform. The composition of the beads may include high, medium or low acoustic contrast material. The chemistry of the functional material may be compatible with existing processes.

Description

生体物質の分離は様々な状況で適用されてきた。例えば、タンパク質を他の生体物質から分離するための分離技術は、多くの分析プロセスにおいて使用されている。   Separation of biological materials has been applied in various situations. For example, separation techniques for separating proteins from other biological materials are used in many analytical processes.

生体物質の分離は、流体チャンバ内に分散されて組換えタンパク質、モノクローナル抗体または細胞などの特定のターゲット物質と結合する機能性物質によって達成することができる。親和性タンパク質でコーティングされたマイクロキャリアなどの機能性物質は、音響定在波の節および腹で捕捉される。このアプローチにおいて、機能性物質は非接触で（例えば、機械的なチャネル、導管、ピンセットなどを使用しないで）捕捉される。   Separation of biological materials can be achieved by functional materials that are dispersed within the fluid chamber and that bind specific target materials such as recombinant proteins, monoclonal antibodies or cells. Functional substances such as microcarriers coated with affinity proteins are trapped in the nodes of the acoustic standing wave and the abdomen. In this approach, the functional material is captured contactlessly (eg, without the use of mechanical channels, conduits, tweezers, etc.).

添付の図面を参照して、図面を以下でより詳細に説明する。   The drawings are described in more detail below with reference to the accompanying drawings.

図１は、磁場において常磁性ビーズを使用する分離プロセスの図である。FIG. 1 is a diagram of a separation process using paramagnetic beads in a magnetic field. 図２は、音響場において音響ビーズを使用する分離プロセスの図である。FIG. 2 is a diagram of a separation process using acoustic beads in an acoustic field. 図３は、ビーズとＣＤ３＋Ｔ細胞複合体の画像である。FIG. 3 is an image of beads and CD3 + T cell complex. 図４は、選択の特異性を実証するためのＣＤ３−Ｔ細胞を含まないビーズの画像である。Figure 4 is an image of beads without CD3-T cells to demonstrate the specificity of the selection. 図５は、ストレプトアビジンとビオチンの共役結合体で利用可能な不均一なビーズの画像である。FIG. 5 is an image of heterogeneous beads available with a conjugated conjugate of streptavidin and biotin. 図６は、均一なアガロースビーズの画像である。FIG. 6 is an image of uniform agarose beads. 図７は、ビーズを処理するための小型音響システムの写真である。FIG. 7 is a photograph of a miniature acoustic system for processing beads. 図８は、分離結果の写真である。FIG. 8 is a photograph of the separation result. 図９は、ビーズと共に使用することができる親和性技術の図である。FIG. 9 is a diagram of an affinity technique that can be used with beads. 図１０は、互いに複合体を形成するストレプトアビジン共役結合ビーズおよびビオチン共役結合ビーズの顕微鏡写真である。FIG. 10 is a micrograph of streptavidin-conjugated and biotin-conjugated beads that form a complex with each other. 図１１は、互いに複合体を形成するストレプトアビジン共役結合ビーズおよびビオチン共役結合ビーズの顕微鏡写真である。FIG. 11 is a photomicrograph of streptavidin-conjugated and biotin-conjugated beads forming a complex with each other. 図１２は、互いに複合体を形成するストレプトアビジン共役結合ビーズおよびビオチン共役結合ビーズの顕微鏡写真である。FIG. 12 is a micrograph of streptavidin-conjugated beads and biotin-conjugated beads that form a complex with each other. 図１３は、赤血球、樹状細胞およびＴ細胞が同定された細胞懸濁液の顕微鏡写真である。FIG. 13 is a micrograph of a cell suspension in which red blood cells, dendritic cells and T cells were identified. 図１４は、細胞の明視野像の顕微鏡写真である。FIG. 14 is a micrograph of a bright field image of cells. 図１５は、細胞に結合した抗ＣＤ４抗体の緑色蛍光の明視野像の顕微鏡写真である。FIG. 15 is a micrograph of a bright field image of green fluorescence of anti-CD4 antibody bound to cells. 図１６は、細胞の明視野像の顕微鏡写真である。FIG. 16 is a micrograph of a bright field image of cells. 図１７は、細胞に結合した抗ＣＤ４抗体のマゼンタ色蛍光の明視野像の顕微鏡写真である。FIG. 17 is a photomicrograph of a bright-field image of magenta fluorescence of anti-CD4 antibody bound to cells. 図１８は、過剰なビーズと過剰な細胞とを含む環境におけるビーズ−細胞複合体の例を示す一連の顕微鏡写真である。FIG. 18 is a series of photomicrographs showing examples of bead-cell complexes in an environment containing excess beads and excess cells. 図１９は、親和性結合のための活性化の化学反応の例を示す図である。FIG. 19 is a diagram showing an example of an activation chemical reaction for affinity binding.

タンパク質または細胞などの生物学的物質の親和性分離は、マイクロビーズなどの表面に共有結合したリガンド（配位子）を使用することによって達成される。このリガンドは、タンパク質または細胞がマイクロビーズ上のリガンドに結合するようにタンパク質または細胞と相互作用するものである。   Affinity separation of biological substances such as proteins or cells is achieved by using ligands covalently bound to the surface such as microbeads. The ligand is one that interacts with the protein or cell such that the protein or cell binds to the ligand on the microbead.

リガンドは、生体分子とともに複合体を形成する物質である。タンパク質−リガンドの結合において、リガンドは通常、対象のタンパク質上のサイトに結合することによってシグナルを生成する分子であり、その結合は典型的にはターゲットタンパク質の評価に変化をもたらす。リガンドは、タンパク質物質に結合する小さな分子、イオンまたはタンパク質であってもよい。リガンドと結合相手との間の関係は、電荷、疎水性および分子構造の関数である。結合は、イオン結合、水素結合、ファンデルワールス力などの分子間力によって起こる。そのドッキングの会合は、実際には解離によって元に戻すことができる。リガンドとターゲット分子との間の測定できる程度の不可逆的な共有結合は、生物学的システムにおいて例外的である。   A ligand is a substance that forms a complex with a biomolecule. In protein-ligand binding, a ligand is usually a molecule that produces a signal by binding to a site on the protein of interest, which binding typically results in an altered assessment of the target protein. The ligand may be a small molecule, ion or protein that binds to proteinaceous material. The relationship between ligand and binding partner is a function of charge, hydrophobicity and molecular structure. Bonding occurs by intermolecular forces such as ionic bonds, hydrogen bonds, and van der Waals forces. The docking association can actually be reversed by dissociation. The measurable irreversible covalent bond between the ligand and the target molecule is exceptional in biological systems.

受容体に結合し、その受容体の機能を変えて生理学的応答を引き起こすことができるリガンドは、受容体に対するアゴニストと呼ばれる。受容体に結合したアゴニストは、どの程度の生理学的応答を引き起こすことができるかという観点と、生理学的応答を生じさせるために必要なアゴニストの濃度の観点の両方の観点から特徴付けることができる。高親和性のリガンド結合は、リガンド−結合サイトを最大限に占有して生理学的応答を引き起こすには比較的低濃度のリガンドで十分であることを意味する。Ｋｉレベルが低いほど、未結合のリガンドと受容性の抗原との間に化学反応が発生しやすい。低親和性の結合（高Ｋｉレベル）は、結合サイトを最大限に占有してリガンドに対する最大の生理学的応答が達成されるためには比較的高濃度のリガンドが必要とされることを意味する。二価のリガンドは、２つの連結したリガンドとしての分子からなり、科学的研究において受容体タイマーを検出したり、その性質を調べたりするために用いられる。 A ligand that can bind to a receptor and alter the function of that receptor to elicit a physiological response is called an agonist for the receptor. Agonists bound to the receptor can be characterized both in terms of how much physiological response can be evoked and in terms of the concentration of agonist required to elicit the physiological response. High affinity ligand binding means that relatively low concentrations of ligand are sufficient to maximally occupy the ligand-binding site and elicit a physiological response. The lower the K i level, the more likely a chemical reaction will occur between the unbound ligand and the receptive antigen. Low affinity binding (high K i levels) means that relatively high concentrations of ligand are required to maximally occupy the binding site and achieve maximal physiological response to the ligand. To do. Bivalent ligands consist of molecules as two linked ligands and are used in scientific studies to detect and characterize the receptor timer.

Ｔ細胞受容体またはＴＣＲは、Ｔ細胞またはＴリンパ球の表面上に見られる分子であり、主要組織適合遺伝子複合体（ＭＨＣ）の分子に結合したペプチドとしての抗原の断片を認識する役割を有する。ＴＣＲと抗原ペプチドとの間の結合は、比較的親和性が低く、変性的である。   The T cell receptor or TCR is a molecule found on the surface of T cells or T lymphocytes and has a role of recognizing a fragment of an antigen as a peptide bound to a molecule of major histocompatibility complex (MHC). .. The binding between the TCR and the antigenic peptide is relatively low affinity and degenerate.

図１を参照すると、ダイナビーズ（Ｄｙｎａｂｅａｄｓ）の名称で販売されている鉄または強磁性ビーズなどの常磁性ビーズは、親和性抽出を達成するために使用されてきた。機能性物質でコーティングされた磁性ビーズは、磁場を用いてターゲット物質を複雑な混合物から分離できるように、複雑な混合物中の生物学的なターゲットに結合する。ビーズは、様々なターゲットに高い特異性で親和性結合するための分子を担持する。このビーズを複雑な混合物に注入し、培養してターゲットと結合させる。ビーズは、そのビーズに付着したターゲットと共に磁石によって抽出される。   Referring to FIG. 1, paramagnetic beads such as iron or ferromagnetic beads sold under the name Dynabeads have been used to achieve affinity extraction. The magnetic beads coated with the functional substance bind to the biological target in the complex mixture so that the target substance can be separated from the complex mixture using a magnetic field. The beads carry molecules for high specific affinity binding to various targets. The beads are injected into a complex mixture, incubated and allowed to bind to the target. The beads are extracted by the magnet with the target attached to the beads.

例えばダイナビーズ（Ｄｙｎａｂｅａｄｓ）のようなミクロサイズのビーズが利用可能であり、そのサイズは４．５μｍ程度である。また、例えばミルテニー（Ｍｙｌｔｅｎｙｉ）のようなナノサイズのビーズを使用してもよく、そのサイズは５０ｎｍ程度である。使用可能な親和性分子のいくつかとしては、抗体、アプタマー、オリゴヌクレオチド、受容体などが挙げられる。親和性結合のターゲットとしては、生体分子、細胞、エキソソーム、薬物などが挙げられる。   For example, micro-sized beads such as Dynabeads can be used, and the size thereof is about 4.5 μm. In addition, nano-sized beads such as Milltenyi may be used, and the size thereof is about 50 nm. Some of the affinity molecules that can be used include antibodies, aptamers, oligonucleotides, receptors and the like. Affinity binding targets include biomolecules, cells, exosomes, drugs, and the like.

図２を参照すると、音響コントラストおよび親和性が高い化学的性質を有するビーズが図示されている。これらの音響ビーズは、機能性物質のコーティングまたは親和性結合用の組成物を有することに関して、磁性ビーズと全く同じ方法で使用することができる。音響ビーズは、音響場で複雑な混合物または流体から抽出されるように設計されている。音響ビーズは、磁性ビーズを使用する細胞製造、生化学、診断、センサーなどにおいて開発された全ての用途に直接使用することができる。   Referring to FIG. 2, beads having chemistry with high acoustic contrast and affinity are illustrated. These acoustic beads can be used in exactly the same way as magnetic beads with respect to having a coating for functional substances or a composition for affinity binding. Acoustic beads are designed to be extracted from a complex mixture or fluid in an acoustic field. The acoustic beads can be directly used for all applications developed in cell manufacturing, biochemistry, diagnostics, sensors, etc. using magnetic beads.

音響ビーズは、磁性ビーズで使用されるのと同じ表面および親和性の化学的性質を使用することができる。磁性ビーズから音響ビーズに容易に置き換えできるため、応用が簡易になるだけでなく、その応用の承認が簡易になるなど、多くの利点を有する。   Acoustic beads can use the same surface and affinity chemistries used in magnetic beads. Since magnetic beads can be easily replaced with acoustic beads, there are many advantages such as not only simplification of application but also simplification of approval of the application.

音響ビーズは生体適合性を有してもよい。そのようなビーズは様々に異なるサイズで製造することができるので、傾斜場（ａｎｇｌｅｄ−ｆｉｅｌｄ）分別技術を用いて提供され得るような、サイズを区別する音響場におけるサイズに基づく連続的な分離が可能になる。音響ビーズは密閉型の音響ベースシステムと組み合わせることができ、この組み合わせにより、治療用細胞の製造の最初から最後まで連続したサイクルを行うことができる。この機能は、現存する親和性の化学的性質の使用をそのまま維持しながら音響ビーズに直接移すことができ、磁性ビーズによる抽出に代わる代替手段を提供する。音響ビーズは、分離工程における消耗品であってもよい。   The acoustic beads may be biocompatible. Since such beads can be manufactured in a variety of different sizes, there is a continuous size-based separation in size-sensitive acoustic fields, such as can be provided using angled-field fractionation techniques. It will be possible. The acoustic beads can be combined with a closed acoustic base system, which allows a continuous cycle from the beginning to the end of therapeutic cell production. This feature can be transferred directly to acoustic beads while preserving the use of existing affinity chemistries, providing an alternative to magnetic bead extraction. The acoustic beads may be consumables in the separation process.

一例では、患者の血液からＣＤ３＋Ｔ細胞を抽出するために、公表済みのメモリアル・スローンケタリングがんセンター（ＭＳＫＣＣ）プロトコルを使用して概念実証（Ｐｒｏｏｆ ｏｆ Ｃｏｎｃｅｐｔ）試験が行われた。この試験では、常磁性ビーズが使用され、磁場が音響場に置き換えられた。患者の血液からＣＤ３＋Ｔ細胞を抽出するプロセスは、ＣＡＲ（キメラ抗原受容体）Ｔ細胞の製造に不可欠な部分である。現在のプロセスは市販のＣＤ３ダイナビーズ（Ｄｙｎａｂｅａｄｓ）に基づいている。この試験では、血液ではなく培養液で実験を行うなど、プロトコルの違いを最小限に抑えるための努力が払われた。ＣＡＲＴ細胞製造におけるいくつかの工程は培養液から行われるので、差異は減少したと考えられる。Ｔ細胞を「音響的に見えない」ようにするか、または音響場の影響を受けにくくするために、溶媒密度を高めた。ダイナビーズ（Ｄｙｎａｂｅａｄｓ）のサイズが小さいと、細胞と同様の音響コントラストが得られるため、分離の許容誤差が小さくなる。試験では、ジャーカット（Ｊｕｒｋａｔ）ＣＤ３＋およびＣＤ３−Ｔ細胞株を、典型的な例として用いた。ＣＤ３−細胞は、非特異的な捕捉に対応する対照として用いた。   In one example, a Proof of Concept test was performed using the published Memorial Sloan-Kettering Cancer Center (MSKCC) protocol to extract CD3 + T cells from patient blood. In this test, paramagnetic beads were used and the magnetic field was replaced by an acoustic field. The process of extracting CD3 + T cells from a patient's blood is an integral part of the production of CAR (chimeric antigen receptor) T cells. The current process is based on the commercially available CD3 Dynabeads. In this test, efforts were made to minimize protocol differences, such as conducting experiments in culture rather than blood. Differences are believed to have diminished, as some steps in CART cell production are performed from culture. Solvent densities were increased to make the T cells "acoustic invisible" or less susceptible to acoustic fields. If the size of the Dynabeads is small, the same acoustic contrast as that of cells can be obtained, so that the separation tolerance is small. In the study, Jurkat CD3 + and CD3-T cell lines were used as a typical example. CD3-cells were used as a control for non-specific capture.

ここで図３および図４を参照すると、前記試験の結果の画像が示されている。細胞懸濁液は、ＣＤ３＋細胞と結合するＣＤ３ダイナビーズと共に培養した。この混合物が音響システムを通過することで、（細胞を含むまたは含まない）磁性ビーズを捕捉した。集めた細胞は培養中でうまく増殖した。図３および図４の画像は、明視野像と蛍光像とを重ね合わせて得られる。ビーズはわずかに赤みを帯びた自己蛍光を有する黒色である。生きている細胞は蛍光赤色である。ビーズの直径は４．５ミクロンである。図３は、ビーズとＣＤ３＋Ｔ細胞複合体を示し、この技術の効率を実証している。図４は、ＣＤ３−Ｔ細胞が抽出されていないことを示し、この技術の特異性および選択性を実証している。   Referring now to Figures 3 and 4, an image of the results of the test is shown. The cell suspension was incubated with CD3 Dynabeads that bind to CD3 + cells. The magnetic beads (with or without cells) were captured as the mixture passed through the acoustic system. The collected cells grew well in culture. The images of FIGS. 3 and 4 are obtained by superimposing the bright field image and the fluorescent image. The beads are black with a slight reddish autofluorescence. Living cells are fluorescent red. The beads have a diameter of 4.5 microns. Figure 3 shows beads and CD3 + T cell complexes, demonstrating the efficiency of this technique. FIG. 4 shows that CD3-T cells were not extracted, demonstrating the specificity and selectivity of this technique.

ここで図５および図６を参照すると、音響ビーズを用いた試験の結果が示されている。この試験では、アガロースビーズを音響ビーズとして使用した。これらのビーズは、いくつかの製造業者から市販されており、常磁性ではないか、または、鉄や強磁性体をほとんど含有していない。あるアガロースビーズでは、抗体が付着しやすくなるように表面が改変されている。それらはまた、治療のソルーションにとって重要な生体適合性物質で構成されている。図５は、ストレプトアビジンとビオチンの共役結合体で利用可能な、比較的安価で不均一（２０〜１５０μｍ）な市販のＡＢＴビーズを示している。図６は、セルモザイク（ＣｅｌｌＭｏｓａｉｃ）アガロースビーズを示している。これは比較的高価で均一（２０〜４０μｍ）になる傾向があり、オーダーによって任意に改変させて構成することができる。   Referring now to Figures 5 and 6, the results of tests with acoustic beads are shown. In this test, agarose beads were used as acoustic beads. These beads are commercially available from several manufacturers and are not paramagnetic or contain little iron or ferromagnets. The surface of some agarose beads has been modified to facilitate attachment of antibodies. They are also composed of biocompatible substances important for therapeutic solutions. FIG. 5 shows relatively inexpensive and heterogeneous (20-150 μm) commercially available ABT beads that can be used in a conjugated conjugate of streptavidin and biotin. FIG. 6 shows Cell Mosaic agarose beads. This tends to be relatively expensive and uniform (20 to 40 μm), and can be arbitrarily modified and configured according to the order.

音響ビーズは、多次元音響定在波などの音響場内に捕捉することができる。図７を参照すると、音響の応用のために開発された小型音響システムが示されており、このシステムは音響ビーズを捕捉するために使用される。前記システムをより小さいサイズにすることにより、大量の高価な試薬の必要性を減らすことができ、少量のサンプルの処理が可能になる。   Acoustic beads can be trapped within an acoustic field such as a multidimensional acoustic standing wave. Referring to FIG. 7, there is shown a miniature acoustic system developed for acoustic applications, which system is used to capture acoustic beads. The smaller size of the system reduces the need for large volumes of expensive reagents and allows the processing of small sample volumes.

図８を参照すると、音響システム内で捕捉されていない（左チューブ）および捕捉された（右）セルモザイク（ＣｅｌｌＭｏｓａｉｃ）アガロースビーズが示されている。音響システムの捕捉効率は９０％以上になる。   Referring to FIG. 8, uncaptured (left tube) and captured (right) Cell Mosaic agarose beads in the acoustic system are shown. The acquisition efficiency of the acoustic system is over 90%.

図９を参照すると、音響ビーズの活性化に対する柔軟なアプローチが示されている。このアプローチでは、ストレプトアビジン−ビオチン複合体を用いて抗体をアガロースビーズに結合させる。この複合体は生化学で広く使用されており、非常に安定している。共役結合ストレプトアビジンを有するアガロースビーズは、抗体−ビオチン共役結合体と同様に市販されている。   Referring to FIG. 9, a flexible approach to acoustic bead activation is shown. In this approach, a streptavidin-biotin complex is used to attach the antibody to agarose beads. This complex is widely used in biochemistry and is very stable. Agarose beads with conjugated streptavidin are commercially available as are antibody-biotin conjugated conjugates.

ストレプトアビジンビーズおよびビオチンビーズの機能性を評価した。図１０〜図１２を参照すると、予想通り、混合時に互いに複合体を形成するストレプトアビジン共役結合ビーズおよびビオチン共役結合ビーズが示されている。   The functionality of streptavidin beads and biotin beads was evaluated. Referring to Figures 10-12, streptavidin-conjugated and biotin-conjugated beads that complex with each other upon mixing are shown, as expected.

懸濁液からＣＤ４＋およびＣＤ８＋（それぞれ「ヘルパー」Ｔ細胞および「キラー」Ｔ細胞）を独立して単離し、それらを効果的な治療の観点から所望の比率で混合することが望ましい場合がある。この目的のために、ＣＤ４受容体およびＣＤ８受容体に対する親和性を有する音響ビーズを提供することができる。一実施例を得るための試験は、マウスの脾臓から調製した細胞懸濁液を用いて行った。図１３を参照すると、赤血球、樹状細胞およびＴ細胞が同定されている。インビトロジェン除去キットを使用して、約２０００万（２０ ｍｉｌｌｉｏｎ（Ｍ））および１８００万（１８Ｍ）のＣＤ４＋Ｔ細胞およびＣＤ８＋Ｔ細胞がそれぞれ４つの脾臓から単離された。両方の細胞株は増殖することができ、ＣＤ４およびＣＤ８のＴ細胞は両方とも約８．２〜８．６μｍである。   It may be desirable to independently isolate CD4 + and CD8 + (“helper” T cells and “killer” T cells, respectively) from the suspension and mix them in the desired ratios in terms of effective therapy. To this end, acoustic beads can be provided that have an affinity for the CD4 and CD8 receptors. The test for obtaining one example was carried out using a cell suspension prepared from mouse spleen. Referring to FIG. 13, red blood cells, dendritic cells and T cells have been identified. Using the Invitrogen Depletion Kit, approximately 20 million (20 million (M)) and 18 million (18M) CD4 + and CD8 + T cells were isolated from four spleens, respectively. Both cell lines are capable of expansion, both CD4 and CD8 T cells are approximately 8.2-8.6 μm.

この試験では、ＣＤ４＋およびＣＤ８＋の単離細胞を免疫学的に検証した。図１４および図１５を参照すると、ＣＤ４受容体の存在を確認できる。マウスの脾臓から精製した後に単離されたＣＤ４のＴ細胞の量を推定するために、アレクサ４８８抗ＣＤ４抗体が使用された。図１４は、焦点面内に細胞の小円を有する明視野像を示す。図１５は、細胞に結合した抗ＣＤ４抗体の蛍光を示す。図１６は、焦点面内に細胞の小円を有する明視野像を示す。図１７は、細胞に結合した抗ＣＤ４抗体の蛍光を示す。図１５及び図１７それぞれにおける緑及びマゼンタの互いに異なる色により、結果の多重分析、たとえばＣＤ４／ＣＤ８比分析ができる。   In this study, CD4 + and CD8 + isolated cells were immunologically validated. With reference to FIGS. 14 and 15, the presence of the CD4 receptor can be confirmed. The Alexa488 anti-CD4 antibody was used to estimate the amount of CD4 T cells isolated after purification from mouse spleen. FIG. 14 shows a bright field image with small circles of cells in the focal plane. Figure 15 shows the fluorescence of anti-CD4 antibody bound to cells. FIG. 16 shows a bright field image with small circles of cells in the focal plane. FIG. 17 shows the fluorescence of anti-CD4 antibody bound to cells. The different colors of green and magenta in FIGS. 15 and 17, respectively, allow for a multiple analysis of the results, eg a CD4 / CD8 ratio analysis.

ここで図１８を参照すると、ストレプトアビジン共役結合アガロースビーズをビオチン共役結合の抗ＣＤ３抗体およびＣＤ３＋ジャーカット（Ｊｕｒｋａｔ）Ｔ細胞と共に用いた試験の結果が示されている。ビーズと細胞の親和性の組み合わせが明確に図示されている。混合物から細胞を抽出するために、ビーズを音響場で分離することができる。   Referring now to FIG. 18, the results of tests using streptavidin-conjugated agarose beads with biotin-conjugated anti-CD3 antibody and CD3 + Jurkat T cells are shown. The bead-cell affinity combination is clearly illustrated. The beads can be separated in an acoustic field to extract cells from the mixture.

音響システムにおける音響親和性ビーズを使用した概念実証および性能の検証が示されている。開示された方法およびシステムでは、市販の試薬および現在利用可能な音響システムが使用できる。親和性は、任意のタイプの所望のＴ細胞またはマーカーをターゲットとすることができ、そのＴ細胞またはマーカーとしては、ＣＤ３＋、ＣＤ４＋、ＣＤ８＋が挙げられる。音響ビーズは、高、中または低のコントラスト係数を有してもよく、このコントラスト係数は、例えばビーズが音響の節または腹に向かって促されるか、または、ビーズが音響場を通過するかなど、ビーズが音響場にどのように応答するかについて影響を及ぼし得るものである。   Proof of concept and verification of performance using acoustically compatible beads in an acoustic system is shown. The disclosed methods and systems can use commercially available reagents and currently available acoustic systems. The affinity can be targeted to any type of desired T cell or marker, including T3 cells, CD4 +, CD8 +. The acoustic beads may have a high, medium or low contrast coefficient, such as whether the beads are encouraged towards the acoustic node or antinode, or whether the beads pass through an acoustic field. , Which can influence how the beads respond to the acoustic field.

ビーズは、様々な物質および組み合わせから構成し、音響性能および生体適合性との最適な相性について開発できるようにしてもよい。ビーズは、分離、選別、または、分離プロセスにおいて有用な他の任意の機能のために、処理してもよい。調整された音響システムと共に使用されるとき、特別に設計された音響ビーズの性能は、常磁性ビーズの性能に匹敵するか、または、その常磁性ビーズの性能を超えることができる。   The beads may be composed of various materials and combinations, allowing them to be developed for optimal compatibility with acoustic performance and biocompatibility. The beads may be treated for separation, sorting, or any other function useful in the separation process. When used with a tuned acoustic system, the performance of specially designed acoustic beads can be comparable to, or exceed, that of paramagnetic beads.

既存の化学物質を音響ビーズと共に使用し、更にサイズおよび構造の均一性の仕様と組み合わせて使用し、音響性能および分離性能に関して所望の結果が得られるようにしてもよい。ビーズは、音響効率を高めるために複合構造物から構成してもよい。音響システムは、熱管理とともに、常磁性ビーズ単独では不可能な結果を得るための流体工学の使用により、小さいサイズを管理できる柔軟性を有する。音響ビーズ及び単純化された処理それぞれの生体適合性および／または生分解性により、ＣＡＲＴ細胞の製造のための既存のハードウェアとの統合が可能になる。親和性音響ビーズは様々な環境で使用することができ、その環境としては、例えば、ターゲット細胞を混入した動物の血液およびマウスの脾臓抽出物などのモデル環境が挙げられる。音響ビーズは、このように既存のシステムと協働して使用してもよく、目的の用途向けに設計および製造してもよい。ビーズは、音響的に活性または不活性のコアを有してもよく、ビーズ自体は、高、中または低の音響コントラスト用に構成してもよい。ビーズのサイズは、分離性と親和性との組み合わせに対して構成してもよく、例えば、特定のサイズのビーズは特定の生体物質をターゲットとする機能性物質を含んでもよく、別のサイズのビーズは別の生体物質をターゲットとするように機能化されてもよく、それぞれのサイズのビーズは閉鎖系または流動系において同時にかつ連続的に分離できるようにしてもよい。ビーズは、狭い範囲または比較的広い範囲で均一なサイズ分布になるように設計してもよい。また、様々な親和性化学物質を使用してもよく、その親和性化学物質としてはストレプトアビジン−ビオチン複合体、免疫グロブリンまたはアプタマーが挙げられる。ビーズは製造容易性および／または保存期間のために設計してもよい。ビーズは、承認済みの化学物質を使用する既知のシステムに容易に統合できるように、承認済みの化学物質と共に使用してもよい。   Existing chemistries may be used with acoustic beads and in combination with size and structural uniformity specifications to achieve desired results with respect to acoustic and separation performance. The beads may be composed of composite structures to enhance acoustic efficiency. Acoustic systems have the flexibility to manage small sizes through the use of fluid engineering to achieve results not possible with paramagnetic beads alone, as well as thermal management. The biocompatibility and / or biodegradability of each of the acoustic beads and the simplified process allows integration with existing hardware for the production of CART cells. Affinity acoustic beads can be used in a variety of environments, including, for example, model environments such as target blood-contaminated animal blood and mouse spleen extracts. The acoustic beads may thus be used in cooperation with existing systems and may be designed and manufactured for the intended application. The beads may have an acoustically active or inactive core, and the beads themselves may be configured for high, medium or low acoustic contrast. The size of the beads may be configured for a combination of separability and affinity, for example, beads of a particular size may contain a functional material that targets a particular biological material, and beads of a different size. The beads may be functionalized to target different biological materials, and beads of each size may be capable of simultaneous and sequential separation in closed or flow systems. The beads may be designed to have a uniform size distribution over a narrow or relatively wide range. Also, a variety of affinity chemistries may be used, including streptavidin-biotin complex, immunoglobulins or aptamers. The beads may be designed for manufacturability and / or shelf life. The beads may be used with approved chemicals so that they can be easily integrated into known systems that use approved chemicals.

図１９を参照すると、活性化の化学反応を例示する図が示されている。この図示された活性化の化学反応は、本明細書に記載された音響親和性ビーズに適用できる。   Referring to FIG. 19, a diagram illustrating the activation chemistry is shown. This illustrated activation chemistry is applicable to the acoustic affinity beads described herein.

上述の方法、システム、および装置は例である。様々な構成は、必要に応じて様々な手順または構成要素を省略、置換、または追加してもよい。例えば、代替構成においては、方法は説明されたものとは異なる順序で実行されてもよく、様々なステップが追加、省略、または組み合わされてもよい。また、特定の構成に関して説明された特徴は、他の様々な構成において組み合わされてもよい。構成の異なる態様および要素は同様の方法で組み合わされてもよい。また、技術は進化しており、したがって、要素の多くは例であり、本開示または特許請求の範囲を限定するものではない。   The methods, systems, and devices described above are examples. Various configurations may omit, replace, or add various procedures or components as desired. For example, in alternative configurations, the methods may be performed in a different order than those described, and various steps may be added, omitted, or combined. Also, the features described with respect to particular configurations may be combined in various other configurations. Different aspects and elements of construction may be combined in a similar fashion. Also, the technology is evolving and, thus, many of the elements are examples and do not limit the disclosure or claims.

例示的な構成（実施形態を含む）の完全な理解を提供するために、本明細書の説明において具体的な詳細が与えられる。しかしながら、構成はこれらの具体的な詳細なしで実施されてもよい。例えば、構成を不明瞭にすることを避けるために、不必要な詳細なしに、周知のプロセス、構造、および技術が示されている。この説明は例示的な構成のみを提供するものであり、特許請求の範囲、適用性または構成を限定するものではない。むしろ、前述の構成の説明は、説明された技法を実施するための説明を提供する。本開示の趣旨または範囲から逸脱することなく、要素の機能および配置に様々な変更を加えてもよい。   Specific details are given in the description herein to provide a thorough understanding of the exemplary configurations (including the embodiments). However, the configuration may be implemented without these specific details. For example, well-known processes, structures, and techniques are shown without unnecessary detail in order to avoid obscuring the configuration. This description provides example configurations only, and does not limit the scope, applicability, or configurations of the claims. Rather, the foregoing configuration description provides a description for implementing the described techniques. Various changes may be made in the function and arrangement of elements without departing from the spirit or scope of the disclosure.

また、構成は、フロー図またはブロック図として示されるプロセスとして説明されてもよい。それぞれが動作を逐次プロセスとして説明することがあるが、動作の多くは並行してまたは同時に実行することができる。さらに、動作の順序は並べ替えられてもよい。プロセスは、図に含まれていない追加のステージまたは機能を有してもよい。   Also, the configuration may be described as a process shown as a flow diagram or block diagram. Although each describes an operation as a sequential process, many of the operations can be performed in parallel or simultaneously. Further, the order of operations may be rearranged. The process may have additional stages or functionality not included in the figure.

いくつかの構成例を説明してきたが、本開示の趣旨から逸脱することなく、様々な修正形態、代替構成、および等価物を使用してもよい。例えば、上記の要素は、より大きなシステムの構成要素としてもよく、その場合、他の構造またはプロセスが、本発明の適用より優先されるか、またはそうでなければ本発明の適用を修正してもよい。また、上記の要素が考慮される前、その間、またはその後に、いくつかの操作を行ってもよい。したがって、上記の説明は特許請求の範囲を限定するものではない。   Although a number of example configurations have been described, various modifications, alternative configurations, and equivalents may be used without departing from the spirit of the present disclosure. For example, the elements described above may be components of a larger system, in which case other structures or processes may supersede or otherwise modify the application of the invention. Good. Also, some operations may be performed before, during, or after the above factors are considered. Therefore, the above description does not limit the scope of the claims.

Claims (3)

分離プロセスにおいて使用する物質であって、
強磁性物質を含まないビーズと、
ターゲット生体物質を引き付けるための前記ビーズ上の機能性物質と、を備える物質。 A substance used in the separation process,
Beads containing no ferromagnetic material,
A functional substance on the beads for attracting a target biological substance. 物質を分離するシステムであって、
音響場を生成するためのデバイスと、
複数のビーズと、を備え、前記複数のビーズはそれぞれ、前記ビーズに結合した生体物質を含み、前記音響場に存在するときに捕捉され、または、通過するシステム。 A system for separating substances,
A device for generating an acoustic field,
A plurality of beads, each of which includes a biological material bound to the beads and is captured or passed through when present in the acoustic field. 物質を分離する方法であって、
機能性物質を複数のビーズに塗工することと、
前記機能性物質に対して親和性を有する生体物質に前記ビーズをさらし、前記生体物質を前記ビーズに結合させることと、
前記ビーズを音響場にさらして、前記ビーズを捕捉し、または、通過させることと、を含む方法。 A method for separating substances,
Coating functional beads on multiple beads,
Exposing the beads to a biological substance having an affinity for the functional substance, and binding the biological substance to the beads;
Exposing the beads to an acoustic field to capture or pass the beads.
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